B-haloxanthine salts op n-diaikyl



Patented July 8, 1952 8-I-IALOXANTHINE SALTS OF N-DIALKYL- AMINOALKYL- N -ARYL1VIETHYL-a-A MINO PYRIDINE S John W. Cusic, Skokie, 111., assignor to G. n. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application December 10, 1949, Serial No. 132,411 1 18 Claims. 01. 259 253) This invention relates to salts of N-tertiaryaliphatic aminoalkyl N arylmethyl aminopyridines with s h-aloxanthines which contain a hydrogen atom in position 7, and to the production thereof. In particular this invention relates to salts of organic bases of the general structural formula wherein Ar is an aryl radical, Alk is an alkylene radical and R and R are alkyl radicals, with 8- haloxanthines which contain a hydrogen atom in position 7.

This application is a continuation-in-part of my prior applications Serial No. 71,763, filed January 19, 1949, now Patent No. 2,534,235, dated December 19, 1950, and Serial No. 745,630, filed May 2, 1947, now abandoned.

In the foregoing structural formula Ar represents a monocarbocyclic aromatic radical and includes phenyl, p-chlorophenyl, p-bromophenyl, o chlorophenyl, p methoxyphenyl, p ethoxyphenyl, o-methoxyphenyl, 2,4-dimethoxypheny1, 2,4-dichlorophenyl and related radicals of the benzene series. Alk represents a bivalent saturated aliphatic hydrocarbon radical containing at least two and not more than five carbon atoms. It includes alkylene radicals such as ethylene, propylene, butylene, trimethylene, and amylene. R and R are lower alkyl radicals containing not more than eight carbon atoms, and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl and octyl radicals.

It is recognized that organic bases of the fore going structural formula, which are widely used as antihistaminic drugs, elicit certain undesir- A further object is to producesuch salts having enhanced therapeutic efiicacy. Other objects will Another ob,-;

salts exert a potentiating effect and show enhanced activity in combatting the effects of histamine. They are particularly useful in the treatment of anaphylaxis and allergic disorders.

Certain of the salts within the scope of this invention are so free from undesirable side effects that they may be used in the treatment and prevention of motion sickness.

Among the halogenated xanthines to which this invention pertains are the chloro, bromo, and iodo derivatives. of theophylline and related xanthines which have a hydrogen atom in position 7.

In particular this invention is concerned with acidic xanthines such as S-chlorotheophylline 8-bromotheophylline S-chlorox-anthine 3-methyl-8-chloroxanthine 8-bromoxanthine 3-methyl-8-bromoxanthine' 1,3cliethyl-S-bromoxanthine, I 1,3-diethyl-8-chloroxanthine 8-iodotheophylline 8-iodo-1,3-diethylxanthine Compositions of organic bases and haloxanthines are readily prepared by dissolving the base in a suitable solvent and treating the resulting solution with a solution of a halogenated xanthine; Solvents which are satisfactory for this reaction include the lower alcohols and ketones and their mixtures with water, ethers and hydrocarbons. Generally small excesses of' the organic'bases are desirable in. these synthetic procedures. The desired salt generally crystallizes outof the solution on chilling or stand- .ing, or may be precipitated by addition of a solvent such as ether or benzene. A simple and efficient alternative method is that of. heatin together at -100 C. equivalent amounts of the liquid organic base andof the haloxanthine, with good mixing with a'small amount offwateror alcohol. As the materials react the mixture gen-g erally forms a thick paste or granular solid. On

. chilling the prodiib't"becomes hard and solid and be apparent to those skilled in the art in view-of v the disclosure given herein; Y

I have discovered that salts of organic bases of the foregoing formula with haloxanthines produce little effect on the central nervous system and appear to be more useful therapeutically than any of the individual components alonef Such may be broken up, ground to a powder and dried. The compounds of this. invention can also be produced by refluxing a solution of an ammonium On chilling this salt precipitates. 1

The following examples illustratein more de Y tall my invention, but in no way are to be construed as limiting it in spirit or in scope;

Example 1 A mixture of 15v g. of N-fi dimethylaminoethyl- N-benzyl-e-aminopyridine (also known as N- benzyl N,N' dimethyl N a pyridylethylenediamine and as tripelenn-amine), which has Example 2 -The 8-bromotheophylline salt of N-liedimethyl- :aminoethyl-N benzyl-a-aminopyridine is. produced as in Example 1 from 15 g. of N'-'c-di- .nmethylaminoethyl -N-. henzyl a aminopyridine and 12 g. of 8-bromotheopliyllinein 100v cc. of boiling methyl ethyl ketone containing cc. of water. The boiling solution is filtered, evaporated and triturated with: coldether. The residual salt on analysis showed 15.3% bromine; the calculated value is 15.5%.

Example 3 A mixture of 6.5. gflof. .N-p-chlorobenz'yl-N-pdimethylaminoethyl-a-aminopyridine, which has the formula oni 4n lia-nd 4 g." of 8-chlorox'ahthine: areidissolve'd: in a :rboilingsmixture of 50 cc; of methyl 'ethyl ketone, 1 00. 'ofrethanoli and 5rcc'.0f-1water. Thezhot '5 solution: is :filtered': and; evaporated on asteam T iba'th. :The "residue? ofi'the 8 =-chloroxa'nthine salt zofN-pechlorobenzyl NQN dimethyl-N a i-pyridylethylenediamine is washed with: coldalcohol, tritu1ated"with *ether' and' dried. sample on ianalys'is showed 14.99 ch'lorine ;i.the'. calculated value' is -14.87%.

-'E':rample 4 'fil he 8-.chlorotheophylline saltof. N-benzyl-N- c diethylaminoethyl-a-aminopyridine, whichhas ahe iormula ,is produced asin Example lffrom' 1 5'. g. of the base andllO' g. of 8-chlorotheophylline. After isolation'itis 'triturated with' ether and dried. A sample on analysis'showed 6.97% chlorine; the calculated value 'is 7.13%.

It is further dried in a desic-" Example 5 THPQwCH.

and/1. g. of S-chlorotheophylline are dissolved in 50 cc. of boiling methyl ethyl ketone containing 2 cc. of water. The boiling solution is filtered and evaporated. The glassy residue of ..thefi-chlorotheophylline salt of N-fl-dimethylaminoethyl-N-p-methoxybenzyl-a-aminopyridine is crystallized from ethyl acetate. It melts at 131-13? 0.

I claim:

1.' An 8-haloxanthine salt of an N-dialkylaminoalkyl N arylmethyl a aminopyridine, wherein the 8-haloxanthine has a hydrogen atom in position 7, the alkyl radicals are lower alkyl radicals and the aryl radical is monocyclic.

2. An S-halotheophylline salt of an N-dialkylaminoalkyl N arylmethyl a aminopyridine, wherein the alkyl radicals are lower alkyl radicals and the aryl radical is monocyclic.

3. An 8-halotheophylline salt of an N-dialkylaminoalkyl-N-benzyl -aamincpyridine, wherein the alkyl radicals are lower alkyl radicals.

4. An B-halotheophylline salt of an N-dimethylaminoalkyl-N-benzyl -aaminopyridine, wherein the alkyl radical is a lower alkyl radical.

5. An 8-chlorotheophylline salt of an N-dimethylaminoalkyl -N- benzyl a aminopyridine, wherein the alkyl radical is a lower alkyl radical.

6. An 8-bromotheophylline. salt of an N-dimethylaminoalkyl -N- benzyl a aminopyridine, wherein the alkyl radical is a lower alkyl radical.

'7. The 8-chlorotheophy1line salt of N-B-dimethylamoniethyl-N-benzyl-a-aminopyridine.

8. The 8-bromotheophylline salt of N-fl-dimethylaminoethyl-N-benzyl-a-aminopyridine.

9. An 8-halotheophylline salt of an N-dialkylaminoalkyl-N-p-alkoxybenzyl -aaminopyridine, wherein the alkyl radicals are lower alkyl radicals.

10. An 8-halotheophylline salt of an N-dimethylaminoalkyl -N-p-methoxybenzyl-a-aminopyridine, wherein the alkyl radical is a lower alkyl radical.

.11. An 8-chlorotheophylline salt of an N-dimethylaminoalkyl -N- methoxybenzyl -aaminopyridine, wherein the alkyl radical is a lower alkyl radical.

12. An 8-bromotheophylline salt of an N-dimethylaminoalkyl-N-p-methoXybenzyl-a-aminopyridine, wherein the alkyl radical is a lower alkyl radical.

13. The 8-chlorotheophylline salt of N-{i-dimethylaminoethyl-N-p-methoxybenzyl-a-aminopyridine.

'14. The 8-bromothe0phylline salt of N-fi dimethylaminoethyl-N-p-methcxybenzyl-a-aminopyridine.

15. The process of producing ah'B-haloxanthine salt of an N-dialkylarninoalkyl-N-aryl- 'methyl-a-aminopyridine which comprises reacting an 8-haloxanthine which contains a hydrogen atom in position 7 with at least one equivalent of an -N dialkylaminoalkyl N arylmethyl-aaminopyridine wherein the alkyl radicals are lower alkyl radicals and the aryl radical is monocyclic, in a hot inert, Water miscible organic solvent, and separating the salt thus formed.

16. The process of producing the B-chlorotheophylline salt of N-fi-dimethylaminoethyl-N- benzyl-aaminopyridine which comprises reacting 8-chlorotheophylline with at least one equivalent of N/3-dimethylaminoethyl N benzyl-aaminopyridine in hot alcohol, and separating the salt thus formed.

17. The process of producing the 8-chlorotheophylline salt of N-,B-dimethylaminoethyl-N- p-methoxybenzy1-a-aminopyridine which comprises reacting B-chlorotheophylline with at least one equivalent of N-fi-dimethylaminoethyl-N-p- 5 diamine.

methoxybenzyl-a-aminopyridine in hot methyl ethyl ketone, and separating the salt thus formed.

18. An B-halotheophylline salt of N-p-methoxybenzyl-N',N'-dimethyl -N-apyridylethylene- JOHN W. CUSIC.

REFERENCES CITED The following references are of record in the 10 file of this patent:

UNITED STATES PATENTS Name Date Cusic Feb. 28, 1950 Number 

1. AN 8-HALOXANTHINE SALT OF AN N-DIALKYLAMINOALKYL - N - ARYLMETHYL - A - AMINOPYRIDINE, WHEREIN THE 8-HALOXANTHINE HAS A HYDROGEN ATOM IN POSITION 7, THE ALKYL RADICALS ARE LOWER ALKYL RADICALS AND THE ARYL RADICAL IS MONOCYCLIC.
 15. THE PROCESS OF PRODUCING AN 8-HALOXANTHINE SALT OF AN N-DIALKYLAMINOALKYL-N-ARYLMETHYL-A-AMINOPYRIDINE WHICH COMPRISES REACTTING AN 8-HALOXANTHINE WHICH CONTAINS A HYDROGEN ATOM IN POSITION 7 WITH AT LEAST ONE EQUIVALENT OF AN N - DIALKYLAMINOALKYL - N - ARYLMETHYL-AAMINOPYRIDINE WHEREIN THE ALKYL RADICALS ARE LOWER ALKYL RADICALS AND THE ARYL RADICAL IS MONOCYCLIC, IN A HOT INERT, WATER MISCIBLE ORGANIC SOLVENT, AND SEPARATING THE SALT THUS FORMED. 